A proteome-scale map of the SARS-CoV-2-human contactome.
Dae-Kyum KimBenjamin WellerChung-Wen LinDayag SheykhkarimliJennifer J KnappGuillaume DugiedAndreas ZanzoniCarles PonsMarie J TofauteSibusiso B MasekoKerstin SpirohnFlorent LavalLuke LambourneNishka KishoreAshyad RayhanMayra SauerVeronika YoungHridi HalderNora Marín-de la RosaOxana PogoutseAlexandra StrobelPatrick SchwehnRoujia LiSimin T RothballerMelina AltmannPatricia CassonnetAtina G CotéLena Elorduy VergaraIsaiah HazelwoodBetty B LiuMaria NguyenRamakrishnan PandiarajanBushra DohaiPatricia A Rodriguez ColomaJuline PoirsonPaolo GiulianaLuc WillemsMikko TaipaleYves JacobTong HaoDavid E HillChristine BrunJean-Claude TwizereDaniel KrappmannMatthias HeinigClaudia FalterPatrick AloyCaroline DemeretMarc VidalMichael A CalderwoodFrederick P RothPascal Falter-BraunPublished in: Nature biotechnology (2022)
Understanding the mechanisms of coronavirus disease 2019 (COVID-19) disease severity to efficiently design therapies for emerging virus variants remains an urgent challenge of the ongoing pandemic. Infection and immune reactions are mediated by direct contacts between viral molecules and the host proteome, and the vast majority of these virus-host contacts (the 'contactome') have not been identified. Here, we present a systematic contactome map of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the human host encompassing more than 200 binary virus-host and intraviral protein-protein interactions. We find that host proteins genetically associated with comorbidities of severe illness and long COVID are enriched in SARS-CoV-2 targeted network communities. Evaluating contactome-derived hypotheses, we demonstrate that viral NSP14 activates nuclear factor κB (NF-κB)-dependent transcription, even in the presence of cytokine signaling. Moreover, for several tested host proteins, genetic knock-down substantially reduces viral replication. Additionally, we show for USP25 that this effect is phenocopied by the small-molecule inhibitor AZ1. Our results connect viral proteins to human genetic architecture for COVID-19 severity and offer potential therapeutic targets.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- coronavirus disease
- nuclear factor
- endothelial cells
- small molecule
- induced pluripotent stem cells
- toll like receptor
- pluripotent stem cells
- signaling pathway
- gene expression
- immune response
- cell proliferation
- transcription factor
- protein protein
- dna methylation
- early onset
- risk assessment